J. Glenn et al, "Identification of a Prenylation Site in Delta Virus Large Antigen", Science, Vol. 256, 29 May 1992, pp. 1331-1333, discloses that during replication, hepatitis delta virus (HDV) switches from production of small to large delta antigen which is prenylated and packaged into virus particles.
The last four amino acids of large delta antigen are Cys-Arg-Pro-Gln-COOH. This COOH-terminal configuration is termed a CXXX box, where C is cysteine and X is any amino acid.
The CXXX box has been implicated as a substrate for prenyltransferases that add to the cysteine 15 (farnesyl) or 20 (geranylgeranyl) carbon moieties derived from mevalonic acid. (J. A. Glomset et al, Trends Biochem. Sci. 15, 139 (1990); W. A. Maltese, FASEB J. 4, 3319 (1990); S. L. Moores et al, J. Biol. Chem. 266, 14603 (1991)).
Glenn et al determined that large delta antigen undergoes prenylation in cultured cells and thus is a substrate for prenylation which is required for productive viral infection. In fact, Glenn et al found that mutation of Cys.sup.211 (the only cysteine in large delta antigen) in the CXXX box of the large delta antigen abolished both prenylation and viral particle formation. In conclusion, Glenn et al suggest "prenylation as a new target for anti-HDV therapy." As strategies designed to interfere with the prenylation stage of the HDV life cycle, Glenn et al suggest "drugs that inhibit enzymes along the prenylation pathway, and CXXX box analogs." (See page 1332).
Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds," Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway.
Squalene synthetase inhibitors which block the action of squalene synthetase (after the formation of farnesyl pyrophosphate) are disclosed in U.S. Pat. Nos. 4,871,721 and 5,025,003, U.S. application Ser. No. 501,204, filed Mar. 29, 1990, and U.S. application Ser. No. 699,429, filed May 13, 1991.